Microvascular dysfunction is a hallmark of several diseases, including coronary artery disease (CAD or coronary atherosclerosis), most of them with high morbidity and mortality rates. Typically, blood supply and oxygen to the heart are affected, with consequences for longevity and quality of life. Furthermore, in the cascade of developing atherosclerosis, the deterioration of microvascular function is considered one of the first pathophysiological changes, occurring before any detectable morphological abnormalities. Thus, microvascular function is a target of choice for the early detection of atherosclerosis and other diseases affecting the heart such as diabetes, obesity, hypertension and hypercholesterolemia.
Currently, tests for coronary and microvascular function are performed using surrogate markers and physical or pharmacological stress (or vasodilatory) agents. Currently used techniques include electrocardiography (ECG), echocardiography, nuclear cardiology imaging (SPECT and PET), computed tomography (CT), and cardiovascular magnetic resonance (CMR). Surrogate markers are related to contractile function, tracer inflow or blood flow measurements. These are expected to indicate reduced macrovascular or microvascular function including the presence or absence of a significant coronary artery stenosis.
However, the use of physical or vasodilatory stress agents or exercise is contraindicated in some patients and pharmacological stress agents have potential dangerous and undesirable side effects and increase scan time and cost. Furthermore, for visualizing the inflow of blood, nuclear imaging uses a radioactive tracer, and CMR applies an intravenous bolus of an MRI contrast agent. This further impairs patient safety (injection, allergies, side effects) and increases scan preparation time and cost.
Myocardial oxygenation has also been used as a marker for ischemia and microvascular dysfunction. Oxygenation-sensitive CMR (OS-CMR) using the blood oxygen-level-dependent (BOLD) effect allows for non-invasive monitoring of changes in myocardial tissue oxygenation. OS-CMR detects changes in haemoglobin oxygenation by making use of the fact that its magnetic properties change when transitioning from oxygenated to deoxygenated status. While oxygenated haemoglobin (oxyHb) is diamagnetic exhibiting a weak stabilization of the magnetic field surrounding the molecule, de-oxygenated haemoglobin (de-oxyHb) is paramagnetic, de-stabilizing the surrounding field and thereby leading to a loss of magnetic field homogeneity, known as the BOLD effect. CMR protocols sensitive to the BOLD effect show a regional oxygenation-sensitive signal intensity (OS-SI or BOLD-SI) drop in tissues with such a relative increase of de-oxyHb, as seen in myocardial ischemia (Bauer et al. 1999; Wacker et al. 1999; Friedrich et al. 2003; Shea et al. 2005).
Several oxygenation-sensitive approaches have been used to detect coronary artery disease, using myocardial oxygenation changes in response to vasodilation by pharmacological agents such as adenosine or dipyridamole as a marker for myocardial ischemia (Friedrich et al. 2003; Fieno et al. 2004; Wacker et al. 1999; Bauer et al. 1999; Shea et al. 2005). While healthy vessels dilate and lead to an increase in myocardial signal intensity (SI), myocardium subtended by stenotic vessels show a blunted increase or a decrease in myocardial BOLD-SI in response to the vasodilatory trigger (Friedrich et al. 2003; Fieno et al. 2004; Wacker et al. 1999). However, these pharmacological agents have undesirable side effects such as bracycardia, arrhythmia, chest pain, bronchospasm, headache, nausea and heat waves. Furthermore, the injection of such vasoactive substances requires intravenous access and the availability of a medical doctor, additional cost for the vasodilatory agent, additional preparation time, and a risk for adverse events related to the injected agent.
Thus there remains a need for methods and systems for assessing the vascular integrity of the heart and diagnosing heart disease.